Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies

BCL10 体细胞突变在淋巴瘤发生和 BCR 靶向治疗反应中的作用

• 批准号: 10436940
• 负责人: Leandro C Cerchietti
• 金额: $ 54.87万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436940
• 关键词: Acceleration; Affect; Antigens; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BCL1 Oncogene; BCL10 gene; BCL2 gene; BCL6 gene; BCR Signaling Pathway; Binding; Biochemical; Biological; Biology; Bypass; C-terminal; Categories; Cell Line; Cell Survival; Classification; Clinic; Complex; Crystallization; Data; Development; Disease; Docking; Drug Targeting; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Higher Order Chromatin Structure; In Vitro; Induced Mutation; Knowledge; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Missense Mutation; Molecular; Molecular Structure; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mutation; NF-kappa B; Oncogenes; Pathway interactions; Patients; Peptide Hydrolases; Proteins; Proto-Oncogenes; Regimen; Resistance; Rest; Role; Series; Set protein; Signal Pathway; Signal Transduction; Somatic Mutation; Structure; Therapeutic; Toll-like receptors; base; cell growth; design; gain of function; gain of function mutation; genetic profiling; improved; in vivo; inhibitor; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; molecular subtypes; mutant; novel; novel therapeutic intervention; overexpression; p65; polymerization; precision medicine; preclinical development; recruit; response; targeted treatment; treatment strategy; tumor

Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a molecularly heterogenous disease. Two recent genomic profiling studies of large DLBCL patient series subclassified these patients in five distinct genomic groups. Both studies essentially agreed in their classification and described a previously unnoticed subtype reminiscent of Marginal Zone Lymphoma (MZL), namely C1 or BN2 lymphoma. This C1/BN2 subtype is characterized by frequent translocations of BCL6 and activating mutations of NOTCH2 and NF-κB signaling genes. Among the latter, 30% of the patients displayed BCL10 mutations, which are rare in other DLBCL subtypes (<2%) but relatively common in MZL (8%). In fact, BCL10 is critical for MZ B-cell development and its overexpression mediates hyperproliferation and eventually lymphomas of MZ origin. However, the effect of BCL10 mutations on lymphomagenesis has not been studied. BCL10 forms a high order complex (CBM) with CARD11 and MALT1, also lymphoma oncogenes. This complex serves as a docking platform for recruitment and activation of other proteins leading to NF-κB activation. BCL10 somatic mutations in DLBCL can be classified in: CARD domain missense and C-terminus truncating mutants. BCL10 CARD mediates CARD11-BCL10 and BCL10-BCL10 interactions while BCL10 C-terminal domain mediates BCL10-MALT1 interaction. In preliminary studies, both classes of mutants accelerate BCL10 polymerization, rewire complex structure and composition and, induce constitutive activation of NF-κB mediated transcription and MALT1 protease activity. We hypothesize that CARD and C-terminal mutations induce gain-of-function and drive lymphomagenesis by activating CBM complex activity and its downstream signaling pathways including NF-κB and that they will do so through distinct molecular mechanisms. Based in our preliminary results, we predict that: i) BCL10 gain-of- function mutations will enhance CBM complex activity by disrupting BCL10 auto-inhibitory structure through distinct molecular mechanisms based on specific biochemical effects of CARD missense or C-terminal truncating mutations; ii) this will cause acceleration of lymphomagenesis in cooperation with NOTHC2 activating mutations, and iii) BCL10 gain-of-function mutations will confer resistance to classical BCR pathway kinase inhibitors such as Ibrutinib (BTK inhibitor), thus requiring targeting downstream proteins such as MALT1 inhibitors or alternative pathways. Our goals for this proposal are to elucidate the molecular mechanism by which specific BCL10 somatic mutations classes alter the high order molecular structure of the CBM complex, to determine how this impacts MZ B-cell growth and survival to cause lymphomas, and to leverage this information to design of novel therapeutic approaches for C1/BN2 lymphomas.

BCL10 体细胞突变在淋巴瘤发生和 BCR 靶向治疗反应中的作用 抽象的 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的淋巴恶性肿瘤，也是一种分子生物学疾病 异质性疾病。最近两项针对大型 DLBCL 患者系列的基因组分析研究对这些患者进行了细分 患者分为五个不同的基因组。两项研究在分类上基本一致，并描述了 以前未被注意到的亚型让人想起边缘区淋巴瘤 (MZL)，即 C1 或 BN2 淋巴瘤。 这种 C1/BN2 亚型的特点是 BCL6 频繁易位和 NOTCH2 激活突变 和 NF-κB 信号基因。后者中，30%的患者表现出BCL10突变，这是罕见的 在其他 DLBCL 亚型中（<2%），但在 MZL 中相对常见（8%）。事实上，BCL10 对于 MZ B 细胞至关重要 MZ 的发育及其过度表达介导过度增殖并最终介导 MZ 起源的淋巴瘤。 然而，BCL10突变对淋巴瘤发生的影响尚未研究。 BCL10 与 CARD11 和 MALT1（也是淋巴瘤癌基因）形成高阶复合物 (CBM)。这个综合体 作为招募和激活其他蛋白质从而导致 NF-κB 激活的对接平台。 BCL10 DLBCL的体细胞突变可分为：CARD结构域错义突变和C末端截短突变。 BCL10 CARD 介导 CARD11-BCL10 和 BCL10-BCL10 相互作用，而 BCL10 C 端结构域 介导 BCL10-MALT1 相互作用。在初步研究中，两类突变体都会加速 BCL10 聚合，重新连接复杂的结构和组成，并诱导 NF-κB 介导的组成型激活 转录和 MALT1 蛋白酶活性。 我们假设 CARD 和 C 端突变通过以下方式诱导功能获得并驱动淋巴瘤发生： 激活 CBM 复合体活性及其下游信号通路（包括 NF-κB） 因此通过不同的分子机制。根据我们的初步结果，我们预测： i) BCL10 增益- 功能突变将通过破坏 BCL10 自抑制结构来增强 CBM 复合物活性 基于 CARD 错义或 C 末端截短的特定生化效应的不同分子机制 突变； ii) 这将与 NOTHC2 激活突变一起导致淋巴瘤发生加速， iii) BCL10 功能获得突变将赋予对经典 BCR 通路激酶抑制剂的抗性，例如 作为依鲁替尼（BTK 抑制剂），因此需要靶向下游蛋白，例如 MALT1 抑制剂或替代品 途径。 我们此提案的目标是阐明特定 BCL10 体细胞突变的分子机制 类改变 CBM 复合物的高级分子结构，以确定这如何影响 MZ B 细胞 生长和存活引起淋巴瘤，并利用这些信息来设计新的治疗方法 C1/BN2 淋巴瘤的治疗方法。